Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1999 Feb 15;18(4):882–892. doi: 10.1093/emboj/18.4.882

Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.

R Soldi 1, S Mitola 1, M Strasly 1, P Defilippi 1, G Tarone 1, F Bussolino 1
PMCID: PMC1171181  PMID: 10022831

Abstract

Interaction between integrin alphavbeta3 and extracellular matrix is crucial for endothelial cells sprouting from capillaries and for angiogenesis. Furthermore, integrin-mediated outside-in signals co-operate with growth factor receptors to promote cell proliferation and motility. To determine a potential regulation of angiogenic inducer receptors by the integrin system, we investigated the interaction between alphavbeta3 integrin and tyrosine kinase vascular endothelial growth factor receptor-2 (VEGFR-2) in human endothelial cells. We report that tyrosine-phosphorylated VEGFR-2 co-immunoprecipitated with beta3 integrin subunit, but not with beta1 or beta5, from cells stimulated with VEGF-A165. VEGFR-2 phosphorylation and mitogenicity induced by VEGF-A165 were enhanced in cells plated on the alphavbeta3 ligand, vitronectin, compared with cells plated on the alpha5beta1 ligand, fibronectin or the alpha2beta1 ligand, collagen. BV4 anti-beta3 integrin mAb, which does not interfere with endothelial cell adhesion to vitronectin, reduced (i) the tyrosine phosphorylation of VEGFR-2; (ii) the activation of downstream transductor phosphoinositide 3-OH kinase; and (iii) biological effects triggered by VEGF-A165. These results indicate a new role for alphavbeta3 integrin in the activation of an in vitro angiogenic program in endothelial cells. Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix, alphavbeta3 integrin participates in the full activation of VEGFR-2 triggered by VEGF-A, which is an important angiogenic inducer in tumors, inflammation and tissue regeneration.

Full Text

The Full Text of this article is available as a PDF (443.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abedi H., Zachary I. Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem. 1997 Jun 13;272(24):15442–15451. doi: 10.1074/jbc.272.24.15442. [DOI] [PubMed] [Google Scholar]
  2. Albini A., Benelli R., Presta M., Rusnati M., Ziche M., Rubartelli A., Paglialunga G., Bussolino F., Noonan D. HIV-tat protein is a heparin-binding angiogenic growth factor. Oncogene. 1996 Jan 18;12(2):289–297. [PubMed] [Google Scholar]
  3. Albini A., Soldi R., Giunciuglio D., Giraudo E., Benelli R., Primo L., Noonan D., Salio M., Camussi G., Rockl W. The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nat Med. 1996 Dec;2(12):1371–1375. doi: 10.1038/nm1296-1371. [DOI] [PubMed] [Google Scholar]
  4. Arcaro A., Wymann M. P. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem J. 1993 Dec 1;296(Pt 2):297–301. doi: 10.1042/bj2960297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Auger K. R., Serunian L. A., Soltoff S. P., Libby P., Cantley L. C. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell. 1989 Apr 7;57(1):167–175. doi: 10.1016/0092-8674(89)90182-7. [DOI] [PubMed] [Google Scholar]
  6. Bader B. L., Rayburn H., Crowley D., Hynes R. O. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell. 1998 Nov 13;95(4):507–519. doi: 10.1016/s0092-8674(00)81618-9. [DOI] [PubMed] [Google Scholar]
  7. Bhattacharya S., Fu C., Bhattacharya J., Greenberg S. Soluble ligands of the alpha v beta 3 integrin mediate enhanced tyrosine phosphorylation of multiple proteins in adherent bovine pulmonary artery endothelial cells. J Biol Chem. 1995 Jul 14;270(28):16781–16787. doi: 10.1074/jbc.270.28.16781. [DOI] [PubMed] [Google Scholar]
  8. Blystone S. D., Lindberg F. P., Williams M. P., McHugh K. P., Brown E. J. Inducible tyrosine phosphorylation of the beta3 integrin requires the alphaV integrin cytoplasmic tail. J Biol Chem. 1996 Dec 6;271(49):31458–31462. doi: 10.1074/jbc.271.49.31458. [DOI] [PubMed] [Google Scholar]
  9. Brooks P. C., Clark R. A., Cheresh D. A. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994 Apr 22;264(5158):569–571. doi: 10.1126/science.7512751. [DOI] [PubMed] [Google Scholar]
  10. Brooks P. C., Montgomery A. M., Rosenfeld M., Reisfeld R. A., Hu T., Klier G., Cheresh D. A. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994 Dec 30;79(7):1157–1164. doi: 10.1016/0092-8674(94)90007-8. [DOI] [PubMed] [Google Scholar]
  11. Brooks P. C., Strömblad S., Klemke R., Visscher D., Sarkar F. H., Cheresh D. A. Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest. 1995 Oct;96(4):1815–1822. doi: 10.1172/JCI118227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Bussolino F., Di Renzo M. F., Ziche M., Bocchietto E., Olivero M., Naldini L., Gaudino G., Tamagnone L., Coffer A., Comoglio P. M. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol. 1992 Nov;119(3):629–641. doi: 10.1083/jcb.119.3.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Bussolino F., Mantovani A., Persico G. Molecular mechanisms of blood vessel formation. Trends Biochem Sci. 1997 Jul;22(7):251–256. doi: 10.1016/s0968-0004(97)01074-8. [DOI] [PubMed] [Google Scholar]
  14. Clark E. A., Brugge J. S. Integrins and signal transduction pathways: the road taken. Science. 1995 Apr 14;268(5208):233–239. doi: 10.1126/science.7716514. [DOI] [PubMed] [Google Scholar]
  15. Defilippi P., Truffa G., Stefanuto G., Altruda F., Silengo L., Tarone G. Tumor necrosis factor alpha and interferon gamma modulate the expression of the vitronectin receptor (integrin beta 3) in human endothelial cells. J Biol Chem. 1991 Apr 25;266(12):7638–7645. [PubMed] [Google Scholar]
  16. Defilippi P., van Hinsbergh V., Bertolotto A., Rossino P., Silengo L., Tarone G. Differential distribution and modulation of expression of alpha 1/beta 1 integrin on human endothelial cells. J Cell Biol. 1991 Aug;114(4):855–863. doi: 10.1083/jcb.114.4.855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Eliceiri B. P., Klemke R., Strömblad S., Cheresh D. A. Integrin alphavbeta3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis. J Cell Biol. 1998 Mar 9;140(5):1255–1263. doi: 10.1083/jcb.140.5.1255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ensoli B., Gendelman R., Markham P., Fiorelli V., Colombini S., Raffeld M., Cafaro A., Chang H. K., Brady J. N., Gallo R. C. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature. 1994 Oct 20;371(6499):674–680. doi: 10.1038/371674a0. [DOI] [PubMed] [Google Scholar]
  19. Ferrara N., Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4–25. doi: 10.1210/edrv.18.1.0287. [DOI] [PubMed] [Google Scholar]
  20. Friedlander M., Brooks P. C., Shaffer R. W., Kincaid C. M., Varner J. A., Cheresh D. A. Definition of two angiogenic pathways by distinct alpha v integrins. Science. 1995 Dec 1;270(5241):1500–1502. doi: 10.1126/science.270.5241.1500. [DOI] [PubMed] [Google Scholar]
  21. Friedlander M., Theesfeld C. L., Sugita M., Fruttiger M., Thomas M. A., Chang S., Cheresh D. A. Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9764–9769. doi: 10.1073/pnas.93.18.9764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Frisch S. M., Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol. 1997 Oct;9(5):701–706. doi: 10.1016/s0955-0674(97)80124-x. [DOI] [PubMed] [Google Scholar]
  23. Ganju R. K., Munshi N., Nair B. C., Liu Z. Y., Gill P., Groopman J. E. Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells. J Virol. 1998 Jul;72(7):6131–6137. doi: 10.1128/jvi.72.7.6131-6137.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Giancotti F. G. Integrin signaling: specificity and control of cell survival and cell cycle progression. Curr Opin Cell Biol. 1997 Oct;9(5):691–700. doi: 10.1016/s0955-0674(97)80123-8. [DOI] [PubMed] [Google Scholar]
  25. Guo D., Jia Q., Song H. Y., Warren R. S., Donner D. B. Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation. J Biol Chem. 1995 Mar 24;270(12):6729–6733. doi: 10.1074/jbc.270.12.6729. [DOI] [PubMed] [Google Scholar]
  26. Hidai C., Zupancic T., Penta K., Mikhail A., Kawana M., Quertermous E. E., Aoka Y., Fukagawa M., Matsui Y., Platika D. Cloning and characterization of developmental endothelial locus-1: an embryonic endothelial cell protein that binds the alphavbeta3 integrin receptor. Genes Dev. 1998 Jan 1;12(1):21–33. doi: 10.1101/gad.12.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hood J., Granger H. J. Protein kinase G mediates vascular endothelial growth factor-induced Raf-1 activation and proliferation in human endothelial cells. J Biol Chem. 1998 Sep 4;273(36):23504–23508. doi: 10.1074/jbc.273.36.23504. [DOI] [PubMed] [Google Scholar]
  28. Ingber D. E., Folkman J. How does extracellular matrix control capillary morphogenesis? Cell. 1989 Sep 8;58(5):803–805. doi: 10.1016/0092-8674(89)90928-8. [DOI] [PubMed] [Google Scholar]
  29. Jones P. L., Crack J., Rabinovitch M. Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J Cell Biol. 1997 Oct 6;139(1):279–293. doi: 10.1083/jcb.139.1.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Keyt B. A., Berleau L. T., Nguyen H. V., Chen H., Heinsohn H., Vandlen R., Ferrara N. The carboxyl-terminal domain (111-165) of vascular endothelial growth factor is critical for its mitogenic potency. J Biol Chem. 1996 Mar 29;271(13):7788–7795. doi: 10.1074/jbc.271.13.7788. [DOI] [PubMed] [Google Scholar]
  31. Khwaja A., Rodriguez-Viciana P., Wennström S., Warne P. H., Downward J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 1997 May 15;16(10):2783–2793. doi: 10.1093/emboj/16.10.2783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. King W. G., Mattaliano M. D., Chan T. O., Tsichlis P. N., Brugge J. S. Phosphatidylinositol 3-kinase is required for integrin-stimulated AKT and Raf-1/mitogen-activated protein kinase pathway activation. Mol Cell Biol. 1997 Aug;17(8):4406–4418. doi: 10.1128/mcb.17.8.4406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kroll J., Waltenberger J. The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem. 1997 Dec 19;272(51):32521–32527. doi: 10.1074/jbc.272.51.32521. [DOI] [PubMed] [Google Scholar]
  34. Kühn K., Eble J. The structural bases of integrin-ligand interactions. Trends Cell Biol. 1994 Jul;4(7):256–261. doi: 10.1016/0962-8924(94)90124-4. [DOI] [PubMed] [Google Scholar]
  35. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  36. Lampugnani M. G., Resnati M., Raiteri M., Pigott R., Pisacane A., Houen G., Ruco L. P., Dejana E. A novel endothelial-specific membrane protein is a marker of cell-cell contacts. J Cell Biol. 1992 Sep;118(6):1511–1522. doi: 10.1083/jcb.118.6.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Law D. A., Nannizzi-Alaimo L., Phillips D. R. Outside-in integrin signal transduction. Alpha IIb beta 3-(GP IIb IIIa) tyrosine phosphorylation induced by platelet aggregation. J Biol Chem. 1996 May 3;271(18):10811–10815. doi: 10.1074/jbc.271.18.10811. [DOI] [PubMed] [Google Scholar]
  38. Martìn-Padura I., Bazzoni G., Zanetti A., Bernasconi S., Elices M. J., Mantovani A., Dejana E. A novel mechanism of colon carcinoma cell adhesion to the endothelium triggered by beta 1 integrin chain. J Biol Chem. 1994 Feb 25;269(8):6124–6132. [PubMed] [Google Scholar]
  39. Millauer B., Wizigmann-Voos S., Schnürch H., Martinez R., Møller N. P., Risau W., Ullrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993 Mar 26;72(6):835–846. doi: 10.1016/0092-8674(93)90573-9. [DOI] [PubMed] [Google Scholar]
  40. Mitola S., Sozzani S., Luini W., Primo L., Borsatti A., Weich H., Bussolino F. Tat-human immunodeficiency virus-1 induces human monocyte chemotaxis by activation of vascular endothelial growth factor receptor-1. Blood. 1997 Aug 15;90(4):1365–1372. [PubMed] [Google Scholar]
  41. Miyamoto S., Teramoto H., Gutkind J. S., Yamada K. M. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol. 1996 Dec;135(6 Pt 1):1633–1642. doi: 10.1083/jcb.135.6.1633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Muller Y. A., Li B., Christinger H. W., Wells J. A., Cunningham B. C., de Vos A. M. Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7192–7197. doi: 10.1073/pnas.94.14.7192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Parsons J. T. Integrin-mediated signalling: regulation by protein tyrosine kinases and small GTP-binding proteins. Curr Opin Cell Biol. 1996 Apr;8(2):146–152. doi: 10.1016/s0955-0674(96)80059-7. [DOI] [PubMed] [Google Scholar]
  44. Pedram A., Razandi M., Levin E. R. Extracellular signal-regulated protein kinase/Jun kinase cross-talk underlies vascular endothelial cell growth factor-induced endothelial cell proliferation. J Biol Chem. 1998 Oct 9;273(41):26722–26728. doi: 10.1074/jbc.273.41.26722. [DOI] [PubMed] [Google Scholar]
  45. Rousseau S., Houle F., Landry J., Huot J. p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene. 1997 Oct;15(18):2169–2177. doi: 10.1038/sj.onc.1201380. [DOI] [PubMed] [Google Scholar]
  46. Sagawa K., Kimura T., Swieter M., Siraganian R. P. The protein-tyrosine phosphatase SHP-2 associates with tyrosine-phosphorylated adhesion molecule PECAM-1 (CD31). J Biol Chem. 1997 Dec 5;272(49):31086–31091. doi: 10.1074/jbc.272.49.31086. [DOI] [PubMed] [Google Scholar]
  47. Schlaepfer D. D., Hanks S. K., Hunter T., van der Geer P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature. 1994 Dec 22;372(6508):786–791. doi: 10.1038/372786a0. [DOI] [PubMed] [Google Scholar]
  48. Schneller M., Vuori K., Ruoslahti E. Alphavbeta3 integrin associates with activated insulin and PDGFbeta receptors and potentiates the biological activity of PDGF. EMBO J. 1997 Sep 15;16(18):5600–5607. doi: 10.1093/emboj/16.18.5600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Schwartz M. A. Integrins, oncogenes, and anchorage independence. J Cell Biol. 1997 Nov 3;139(3):575–578. doi: 10.1083/jcb.139.3.575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Schwartz M. A., Schaller M. D., Ginsberg M. H. Integrins: emerging paradigms of signal transduction. Annu Rev Cell Dev Biol. 1995;11:549–599. doi: 10.1146/annurev.cb.11.110195.003001. [DOI] [PubMed] [Google Scholar]
  51. Senger D. R., Ledbetter S. R., Claffey K. P., Papadopoulos-Sergiou A., Peruzzi C. A., Detmar M. Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin. Am J Pathol. 1996 Jul;149(1):293–305. [PMC free article] [PubMed] [Google Scholar]
  52. Soker S., Takashima S., Miao H. Q., Neufeld G., Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998 Mar 20;92(6):735–745. doi: 10.1016/s0092-8674(00)81402-6. [DOI] [PubMed] [Google Scholar]
  53. Soldi R., Graziani A., Benelli R., Ghigo D., Bosia A., Albini A., Bussolino F. Oncostatin M activates phosphatidylinositol-3-kinase in Kaposi's sarcoma cells. Oncogene. 1994 Aug;9(8):2253–2260. [PubMed] [Google Scholar]
  54. Soldi R., Primo L., Brizzi M. F., Sanavio F., Aglietta M., Polentarutti N., Pegoraro L., Mantovani A., Bussolino F. Activation of JAK2 in human vascular endothelial cells by granulocyte-macrophage colony-stimulating factor. Blood. 1997 Feb 1;89(3):863–872. [PubMed] [Google Scholar]
  55. Strömblad S., Becker J. C., Yebra M., Brooks P. C., Cheresh D. A. Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin alphaVbeta3 during angiogenesis. J Clin Invest. 1996 Jul 15;98(2):426–433. doi: 10.1172/JCI118808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Takahashi T., Shibuya M. The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene. 1997 May 1;14(17):2079–2089. doi: 10.1038/sj.onc.1201047. [DOI] [PubMed] [Google Scholar]
  57. Terman B. I., Carrion M. E., Kovacs E., Rasmussen B. A., Eddy R. L., Shows T. B. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene. 1991 Sep;6(9):1677–1683. [PubMed] [Google Scholar]
  58. Thiagarajan P., Shapiro S. S., Levine E., DeMarco L., Yalcin A. A monoclonal antibody to human platelet glycoprotein IIIa detects a related protein in cultured human endothelial cells. J Clin Invest. 1985 Mar;75(3):896–901. doi: 10.1172/JCI111789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Thomas K. A. Vascular endothelial growth factor, a potent and selective angiogenic agent. J Biol Chem. 1996 Jan 12;271(2):603–606. doi: 10.1074/jbc.271.2.603. [DOI] [PubMed] [Google Scholar]
  60. Toker A., Cantley L. C. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature. 1997 Jun 12;387(6634):673–676. doi: 10.1038/42648. [DOI] [PubMed] [Google Scholar]
  61. Vuori K., Ruoslahti E. Association of insulin receptor substrate-1 with integrins. Science. 1994 Dec 2;266(5190):1576–1578. doi: 10.1126/science.7527156. [DOI] [PubMed] [Google Scholar]
  62. Waltenberger J., Claesson-Welsh L., Siegbahn A., Shibuya M., Heldin C. H. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem. 1994 Oct 28;269(43):26988–26995. [PubMed] [Google Scholar]
  63. Wary K. K., Mainiero F., Isakoff S. J., Marcantonio E. E., Giancotti F. G. The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell. 1996 Nov 15;87(4):733–743. doi: 10.1016/s0092-8674(00)81392-6. [DOI] [PubMed] [Google Scholar]
  64. Woodard A. S., García-Cardeña G., Leong M., Madri J. A., Sessa W. C., Languino L. R. The synergistic activity of alphavbeta3 integrin and PDGF receptor increases cell migration. J Cell Sci. 1998 Feb;111(Pt 4):469–478. doi: 10.1242/jcs.111.4.469. [DOI] [PubMed] [Google Scholar]
  65. Yamada K. M., Miyamoto S. Integrin transmembrane signaling and cytoskeletal control. Curr Opin Cell Biol. 1995 Oct;7(5):681–689. doi: 10.1016/0955-0674(95)80110-3. [DOI] [PubMed] [Google Scholar]
  66. Zhu X., Ohtsubo M., Böhmer R. M., Roberts J. M., Assoian R. K. Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol. 1996 Apr;133(2):391–403. doi: 10.1083/jcb.133.2.391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES